The broad long-term goal is to elucidate the mechanisms responsible for the dysfunction and loss of neurons in degenerative neurological disorders. In BPAG1 null mouse, axonal degeneration of sensory neurons leads to dramatic and progressive deterioration in motor functions. This null mouse provides us a powerful tool for studying cellular and molecular mechanisms of neurodegeneration. Defining the biological functions of BPAG1 would significantly advance our understanding of pathogenesis. In previous studies, we documented BPAG1n1 and BPAG1n3, which function as cytoskeleton organizing proteins interconnecting all three networks. Most recently, we identified an additional isoform of BPAG1, BPAG1n4, whose functional importance has been suggested by our preliminary studies. We hypothesize that BPAG1n4 plays an important role in axonal transport of vesicles. Ablation of BPAG1 neuronal isoforms leads to disorganization of axonal cytoskeletal networks, disruption of axonal transport of vesicles and failure of target-derived neurotrophic support. This defect culminates in the death of affected neurons. The first AIM will further examine and confirm the subcellular localization of BPAG1n4 at the ultrastructural level. The second AIM is to characterize all potential functions of BPAG1n4. The functional interactions between BPAG1n4 and cytoskeletal proteins will be explored both in vitro and in vivo. The third AIM is to identify the proteins with which BPAG1n4 interact with. The proposed study will enhance our understanding of the biological functions of cytoskeletal organizing proteins in axons and their role(s) in sustaining neuronal survival. We expect to obtain important insights regarding the molecular pathogenesis of the death of neurons that have been deprived of target innervations. Our findings wilt lead to a better understanding and possible treatment for neurodegenerative disorders.